Four major antiepileptic drugs (AEDs) are used for the treatment of epilepsy (epileptic seizures and convulsions): phenytoin, carbamazepine, phenobarbital and valproic acid (VPA). However, about 25% of the patients do not respond to the current medications. Furthermore, AEDs are administered repetitively as chronic treatment and the adverse effects associated with antiepileptic therapy are of a major concern. All the established AEDs are associated with certain rare but severe side effects such as teratogenicity and Valproic acid itself has considerable adverse effects including the potential for fatal hepatotoxicity.
One approach to obtain improved antiepileptic agents has been to prepare the primary amide derivatives of valproic acid and its analogs (M. Bialer, Clin. Pharmacokinet., 20:114-122 (1991)). Valproyl glycinamide (M. Bialer, et al. U.S. Pat. No. 5,585,358, issued Dec. 17, 1996), is currently undergoing clinical trials in epileptic patients that are not seizure-free under the existing AEDs (M. Bialer, S. I. Johannesen, H. J. Kupferberg, R. H. Levy, P. Loiseau and E. Perucca, Epilepsy Res., 34:1-34 (1999)). Amide analogues of valproic acid have been shown to be non-teratogenic.
Taurine (2-aminoethanesulfonic acid) is an inhibitory neurotransmitter in the CNS, but its role has not yet been clearly established. Decreased taurine levels in the urine of epileptic patients and changes in the urinary taurine concentration as a consequence of antiepileptic drug therapy have been described (B. W. Colins, H. O. Goodman, C. H. Swanton and C. N. Remy, Clin. Chem., 34:671-674 (1988)). Taurine has an anticonvulsant effect when administered to the CNS, but it is clinically useless because it is unable to cross the blood brain barrier (BBB) in sufficient quantities. Certain lipophilic taurine derivatives have been disclosed in S. S. Oja, P. Kontro, I. B. Linden and G. Gothoni Eur. J. Pharmacol., 87:191-198, (1983), and L. Ahtee, H. Auvinen, A-R Maenpaa, M-L. Vahala, M. Lehtinen and J. Halmekoski, Acta Pharmacol. Toxicol., 57:96-105, (1985) and Andersen, et al., U.S. Pat. No. 4,556,673 issued Dec. 3, 1985, but these taurine derivatives have not been accepted for use in clinical practice. Certain taurine derivatives have been shown to have several CNS activities, such as effect on the pentobarbital sleeping time and locomotor activity, elevation of the cerebral dopamine concentration and antagonization of the antinociceptive effect of morphine. Taurine itself suppresses neuropathic pain in animal models. These results indicate that new taurine derivatives possess anticonvulsant activity and may have the potential to become new CNS drugs.
Based on the success of VPA and taurine in treatment of nonepileptic disorders it is expected that valproyl taurine derivative will be effective in migraine, neuropathic pain, and mania (bipolar disorders).